In intrathecal delivery of a pharmaceutical agent, the pharmaceutical agent is administered adjacent to the spinal cord in what is referred to as the intrathecal space (which also is referred to as the subarachnoid space). The intrathecal space is filled with the cerebrospinal fluid (CSF), which bathes and protects the brain and spinal cord. In conventional intrathecal delivery systems, a patient may be implanted with a small pump containing the pharmaceutical agent. A catheter extends from the pump and into the intrathecal space at a desired location along the spinal cord depending on the precise condition being treated. The pump operates to deliver the pharmaceutical agent through the catheter and into the CSF within the intrathecal space.
Intrathecal delivery has advantages over oral medication for certain conditions. By administering the pharmaceutical agent intrathecally, the agent may be delivered directly to neural receptors of the spinal cord that control certain biological states. Common examples of intrathecal treatments include treatments for chronic pain relief and blood pressure regulation. By administering the pharmaceutical agent directly to spinal receptors associated with pain, or receptors that control blood pressure (or other suitable receptors for other conditions), such conditions can be treated more efficiently and at less dosages than oral medications for the same condition, which must be digested, absorbed, and travel through the bloodstream.
In conventional intrathecal delivery systems, pumps are controlled to administer the pharmaceutical agent in essentially a continuous and “slow” manner. In this context, a slow delivery tends to be infused at a rate of 0.2 to 0.5 ml/day and an optional patient-controlled bolus delivery of up to about 10 microliters (μL) per minute, which constitutes the approximate upper limit on the delivery rate in conventional intrathecal delivery systems. The result of such a slow and continuous delivery is to administer up to about 0.2-0.6 milliliters per day for a typical intrathecal delivery system.
Although intrathecal delivery of a pharmaceutical agent has certain advantages over oral medication, intrathecal delivery systems have experienced their own drawbacks. Certain significant drawbacks result from the nature of the flow of the CSF within the intrathecal space.
The nature of the flow of the CSF within the intrathecal space has been the subject of substantial study. It has been found that the CSF flow tends to oscillate back and forth in accordance with the cardiac cycle, with minimal if any net movement in a cycle. In particular, during the systole portion of the cardiac cycle, the CSF tends to flow away from the brain, and during the diastole portion of the cardiac cycle, the CSF tends to flow oppositely from systole and toward the brain. The result of this back-and-forth movement is that during a complete cardiac cycle, there is little overall movement of the CSF. There is a minute component of bulk flow of the CSF around the brain and spinal cord, but such bulk flow is negligible as compared to the oscillatory flow, the bulk flow accounting only for less than about 0.5% of the CSF flow.
To a lesser extent as compared to the cardiac cycle, CSF flow also is influenced by the respiratory cycle. During expiration, when the diaphragm is forcing air outward, the abdominal and thoracic pressures are increasing and tend to force the CSF flow toward the brain. Conversely, during inhalation, when the abdominal and thoracic pressures negatively are pulling air inward, CSF flow tends to be away from the brain. Although the influence of the respiratory cycle on CSF flow tends to be significantly less than that of the cardiac cycle, both cycles produce an oscillatory rather than bulk flow. As referenced above, the result of this back-and-forth movement is that during these cycles, there is little overall movement of the CSF, with any component of bulk flow being essentially negligible.
The predominance of the oscillatory nature of the CSF flow has ramifications for intrathecal delivery of a pharmaceutical agent. In particular, with the slow and continuous administering of conventional systems, there is only a slight distance of travel of the pharmaceutical agent from the catheter at the low rates of currently available intrathecal pumps. Accordingly, to ensure delivery of the pharmaceutical agent to the appropriate spinal receptors, the catheter placement must be precise and in close proximity to the target receptors. In addition, the build-up of pharmaceutical agent (particularly opiates) adjacent the catheter, due to the low travel distance, can lead to an adverse complication known as a “granuloma”. A granuloma is a collection of immune cells that build up around the catheter as the catheter/medication is “perceived” by the immune system to be an unwanted foreign body. Granulomas interfere with the effective administering of the pharmaceutical agent and can grow in size to cause nerve damage. As referenced above, this appears to result from the pharmaceutical agent building up adjacent the catheter due to low travel distance caused by the oscillating CSF flow.
Accordingly, current systems for intrathecal delivery of a pharmaceutical agent have been shown to have significant drawbacks.